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D. P. Bingaman, X. Gu, R. A. Landers, W. E. Howe, C. Liu, S. Stacy, C. Romano; AL-39324 Is More Potent and Efficacious Against Ocular NV vs. Other RTKi’s. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1747.
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We compared the preclinical antiangiogenic performance of AL-39324 against 3 other RTKi clinical candidates.
Bovine retinal endothelial cells (BRECs), +/- 25ng/mL VEGF, were treated with 0.1-100nM AL-39324, PTK787 (Novartis), Sutent (Pfizer), CP-547,632 (Pfizer), or vehicle. After 24 hours, the relative levels of viable cells were assayed. Rat model of oxygen-induced retinopathy (OIR): Sprague-Dawley pups were exposed to variable 02 exposure q24hrs from P0-14 and then placed into room air. 1% AL-39324 vs. 0.3, 1 and 3% PTK787, Sutent, and CP-547,632 were tested via a single 5µl intravitreal (ivt) injection at P14. At P20, ADPase-stained retinas were imaged to obtain a median preretinal NV score/treatment group. Mouse model of laser-induced choroidal NV (CNV): Rupture of Bruch’s membrane was induced in C57BL/J mice via focal laser photocoagulation. 1% AL-39324 vs. 1% Sutent was compared using a single 2µl ivt injection immediately post-laser. At day 14 post-laser, all mice were euthanized and computerized analysis of fluorescein-stained choroidal flat-mounts used to define median or mean CNV areas per treatment group. p≤0.05 was considered significant.
In vitro-AL-39324 dose-dependently blocked VEGF-induced increases in viable BRECs, with complete inhibition at 100nM. Sutent and CP-547,632 also showed complete inhibition at 100nM. PTK787 provided only partial inhibition at all doses tested. In the Rat OIR model, all 3 RTKi’s were less potent than AL-39324 in the vehicle used. 1 and 3% Sutent showed 63%, (p=0.053) and 100% (p<0.05), respectively, while 0.3 and 1% CP-547,632 showed only 55% and 50%, respectively (both p<0.05). Dose-dependent cataract formation and local inflammation were found with Sutent and CP-547,632. In the mouse CNV model, 1% Sutent did not inhibit CNV, while 1% AL-39234 significantly reduced CNV lesion size vs vehicle-injected controls by ↓70.6% (p<0.05).
Local treatment with AL-39324 was generally more potent than several of the RTKi’s currently in clinical trials for ophthalmic and non-ophthalmic indications. These results suggest that the receptor inhibition profile and/or the physico-chemical properties of this class impact their effectiveness against pathologic ocular angiogenesis.
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